While endothelium has historically been considered a homogeneous cell layer, there is an increasing appreciation that it exhibits a rich diversity in structure and function. Heterogeneity is apparent between endothelial cells in different organs, in endothelial cells along a single vascular segment within an organ and, indeed, between immediately adjacent cells. This Program Project Grant is founded on the hypothesis that endothelium lining the lung's extra-alveolar and alveolar blood vessels is phenotypically distinct, and that the unique behavior(s) of cells from these different vascular locations is necessary for them to fulfill their sitespecific function(s). We currently possess a limited understanding of how such heterogeneity is achieved to control site-specific vascular demands, particularly in the lung's microvascular compartment. A principal goal in this competitive renewal application is therefore to rigorously determine molecular mechanisms that allow lung microvascular endothelial cells to successfully control their capillary function. Our focus on the microvascular endothelial cell phenotype is based upon the relative paucity of information regarding the behavior of this cell type. We propose four inter-related projects examining different signal transduction cascades that control lung microvascular endothelial cell behavior, including permeability regulation (Stevens, Project 1 and Townsley, Project 4), apoptosis/necrosis (Gillespie, Project 2), and von Willebrand factor secretion (Wu, Project 3). These projects are highly interactive both conceptually and pragmatically. Toward this end, this Program Project Grant draws on emerging developments in different fields of study, and applies these developments to generate new information about how microvascular lung endothelial cells, in particular, respond to inflammation and how they repair following injury. Defining the mechanisms that underlie lung microvascular endothelial cell function will provide insight into the site-specific nature of pulmonary vascular disease, and allow us to ultimately develop rational pharmacological therapies to discretely intervene in the endothelial cell dysfunction that occurs in all known pulmonary vascular diseases.